Therapeutic Potential of ACMSD Inhibitors in NAD+ Deficient Diseases

Min Chen ^{1, 2}

Hua Zhang ^{3, 4}

Pengfei Ji ¹

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Department of Chemistry, Zhejiang University, Hangzhou 310058, China |

Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou 310011, China |

Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China |

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Orthopedics Research Institute, Zhejiang University, Hangzhou 310009, China |

Publication type: Journal Article

Publication date: 2025-02-17

MDPI

Journal: Drugs and Drug Candidates

SJR: —

CiteScore: —

Impact factor: —

ISSN: 28132998

DOI: 10.3390/ddc4010007

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Abstract

Nicotinamide adenine dinucleotide (NAD+) is one of the most essential coenzymes that is widely distributed in human tissues. However, with the progress of aging, the NAD+ level gradually decreases, thus impacting the metabolic dynamics and heightening susceptibility to various pathologies. Increasing NAD+ levels are expected to delay aging and improve age-related degenerative diseases. Amino–carboxylic semialdehyde dehydrogenase (ACMSD) is a key enzyme involved in the de novo synthesis of NAD+. It reduces the intermediate products of the de novo synthesis pathway by catalyzing the degradation of α-amino-β-carboxyethylglutamic acid-ε-semialdehyde (ACMS), thus reducing the production of NAD+. Genetic and pharmacological inhibition of ACMSD has been demonstrated to increase NAD+ levels in vitro and in vivo, thus making it a potential target for the treatment of NAD+-deficient diseases. In this mini-review, we detail the molecular mechanisms regulated by ACMSD. We also discuss the potential efficacy and progress of ACMSD inhibitors in treating aging and age-related diseases.